Antiphlogistic-analgesic plaster comprising triacetin and piroxicam

ABSTRACT

An antiphlogistic-analgesic plaster comprising piroxicam and triacetin and/or triethyl citrate. 
     The antiphlogistic-analgesic plaster of the invention is excellent in percutaneous absorption of piroxicam and hence has an excellent antiphlogistic and analgesic effect.

This application is filed under 35 USC 1.371 of PCT/JP92/01473 filedNov. 11, 1992.

TECHNICAL FIELD

The present invention relates to an antiphlogistic-analgesic plastercomprising piroxicam as an active ingredient, and more particularly toan antiphlogistic-analgesic plaster improved percutaneous absorption ofpiroxicam contained therein.

BACKGROUND ART

Piroxicam is a compound called by a chemical name of4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxideand has an excellent antiphlogistic and analgesic effect. It has hencebeen widely used clinically at present.

Piroxicam is mostly prepared in the form of an oral preparation and inthe forms of a suppository and an ointment in extreme part.

However, the oral preparation has involved a problem of side effectssuch as a disorder of the digestive tract. Although the side effects aresomewhat reduced by the suppository compared with the oral preparation,the disorder of the digestive tract has been still recognized on thesuppository. Moreover, these preparations have been difficult toeffectively deliver their active ingredients to the diseased area. Theointment by which piroxicam can be topically applied has been proposedin order to remedy the above drawbacks involved in the oral preparationand suppository. However, this preparation has also been accompanied bydrawbacks that its dose is inaccurate and its base ingredients adhere toclothes to smear them.

A plaster is the most effective form for percutaneously administeringthe drug to deliver it to the diseased area Japanese Patent ApplicationLaid-Open No 316314/1989 discloses that a plaster in which lornoxicam,tenoxicam, piroxicam or sulindac is incorporated exhibit higherantiphlogistic and analgesic effect compared with a plaster in which anon-steroidal antiphlogistic-analgesic drug such as indomethacin,diclofenac, flurbiprofen or ketoprofen is incorporated. However, itseffect is insufficient and it also offers a problem of physicalproperties as a plaster. Therefore, it is unfit for use and hence notyet provided in the clinical field under circumstances.

As described above, a satisfactory effect has not been successfullyachieved even when piroxicam has been incorporated into a base for aplaster because its percutaneous absorption is poor.

Therefore, it is an object of the present invention to provide apiroxicam-containing plaster excellent in percutaneous absorption ofpiroxicam.

In view of the foregoing circumstances, the present inventors havecarried out an extensive investigation. As a result, it has been foundthat triacetin and triethyl citrate have an effect of facilitating thepercutaneous absorption of piroxicam, thus leading to completion of thepresent invention.

DISCLOSURE OF THE INVENTION

The present invention is directed to an antiphlogistic-analgesic plastercomprising piroxicam and triacetin and/or triethyl citrate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram illustrating the concentration profile of piroxicamin plasma with time at the time plasters obtained in Examples 1-5 andComparative Example 1 were separately applied to the back of a guineapig, and

FIG. 2 is a diagram illustrating the concentration profile of piroxicamin plasma with time at the time plasters obtained in Example 6 andComparative Example 2 were separately applied to the back of a guineapig.

BEST MODE FOR CARRYING OUT THE INVENTION

In the plaster according to the present invention, the amount ofpiroxicam to be incorporated is preferably 0.05-5 wt. %. Besides, theamounts of triacetin and triethyl citrate to be incorporated arepreferably each 0.05-40 wt. %, particularly 0.5-10 wt. %.

As base ingredients for the plaster according to the present invention,may be used base ingredients usually used. No particular limitation isimposed on such base ingredients. However, examples of the baseingredients usually used include water-soluble polymers such as sodiumpolyacrylate, polyacrylic acid, carboxyvinyl polymers, sodiumcarboxymethyl cellulose, polyvinyl alcohol and gelatin; glycols such asglycerin, propylene glycol and polyethylene glycol; cross-linking agentssuch as aluminum hydroxide, aluminum potassium sulfate and aluminumglycinate; purified water; inorganic powders such as kaolin and titaniumoxide; pH adjustors such as citric acid and tartaric acid; surfactantssuch as polyoxyethylene sorbitan monooleate, sorbitan monooleate,polyoxyethylene monooleate and polyoxyethylene hydrogenated castor oil;and the like. Further, penetration enhancers, antiseptics, antifungalpreservatives, antioxidants, flavorants colorants and the like may beadded as needed.

Of these, the water-soluble polymers, glycols, cross-linking agents,purified water, inorganic powders and surfactants are preferablyincorporated in a base in proportions of 1-20 wt. % 1-50 wt. % 0.01-5wt. % 10-90 wt. %, 0-20 wt. % and 0-20 wt. %, respectively.

No particular limitation is imposed on the preparation process of theplaster according to the present invention. It is however prepared by aprocess in which a base is prepared from the above ingredients inaccordance with a method known per se in the art, the base is spread ona backing material, and the surface of the spread base is covered with aprotective film, or a process in which the above base is spread on aprotective film, and the surface of the spread base is covered with abacking material to transfer the base to backing material.

No particular limitation is imposed on the backing material so far as itis a woven fabric, nonwoven fabric, film or sheet having goodflexibility. For example, a woven fabric or nonwoven fabric from fibersof rayon, polyester, polyolefin, polyurethane or the like, polymer film,foamed sheet, or the like may be used. It is preferable to use a backingmaterial having elasticity in all directions. An anchor coat may beapplied to these backing materials as needed.

The thus-obtained plaster of the present invention is stored in a tightcontainer or the like.

Examples

The present invention will hereinafter be described by the followingexamples.

Examples 1-5

Plasters having their corresponding compositions shown in Table 1 wereprepared.

                  TABLE 1    ______________________________________    (wt. %)    Example      1       2       3     4     5    ______________________________________    Piroxicam    0.25    0.25    0.25  0.25  0.25    Glycerin     15.00   15.00   15.00 15.00 15.00    Polyoxyethylene                 1.00    1.00    1.00  1.00  1.00    hydrogenated castor    oil    Triacetin    0.50    2.00    4.00  --    --    Triethyl citrate                 --      --      --    2.00  4.00    Sodium carboxy-                 4.00    4.00    4.00  4.00  4.00    methylcellulose    Sodium polyacrylate                 5.00    5.00    5.00  5.00  5.00    Gelatin      1.00    1.00    1.00  1.00  1.00    Kaolin       4.00    4.00    4.00  4.00  4.00    Aluminum glycinate                 0.15    0.15    0.15  0.15  0.15    Tartaric acid                 2.30    2.30    2.30  2.30  2.30    EDTA.2Na     0.10    0.10    0.10  0.10  0.10    Purified water                 66.70   65.20   63.20 65.20 63.20    Total        100.00  100.00  100.00                                       100.00                                             100.00    ______________________________________

(Preparation process)

Triacetin or triethyl citrate was mixed in polyoxyethylene hydrogenatedcastor oil melted under heat in advance, to which piroxicam was added tostir the resultant mixture (A). Gelatin was dissolved in 40 g ofpurified water heated (B). Sodium carboxymethylcellulose, sodiumpolyacrylate and aluminum glycinate were dispersed in glycerin (C). Themixture (A), the solution (B), the dispersion (C), kaolin, tartaricacid, EDTA. 2Na and the remainder of purified water were intimatelymixed with one another to obtain a base for an antiphlogistic-analgesicplaster. This paste was spread at an amount of 0.1 g/cm² on a nonwovenfabric having weight of 100 g/cm². The surface was then covered with apolyester film to obtain an antiphlogistic-analgesic plaster accordingto the present invention, which contained piroxicam in a proportion of0.25 mg per cm².

Comparative Example 1

A plaster was prepared in the same manner as in Example 1 except thattriacetin was not added.

Test Example 1

The plasters obtained in Examples 1-5 and Comparative Example 1 wereseparately applied to the shaved back (30 cm²) of a male guinea pig(Hartley, aged 4 weeks, weight: 250-300 g) to collect blood through acannule inserted in the jugular vein right before the application andupon elapsed time of 2, 4, 6 and 8 hours after the application, wherebythe concentration of piroxicam in plasma was determined by a highperformance liquid chromatogram to observe the concentration profile ofpiroxicam in plasma with time. The results are shown in FIG. 1.

Example 6

To 2 g of triethyl citrate, were added 0.25 g of piroxicam and 0.1 g ofmethyl para-hydroxybenzoate to intimately stir the resultant mixture(A). To 15 g of glycerin, were added 5 g of sodium polyacrylate and 0.2g of aluminum glycinate to intimately stir the resultant mixture (B).Five grams of a carboxyvinyl polymer were dispersed in 60 g of purifiedwater heated (C). To 10.35 g of purified water heated, were added 2 g ofgelatin and 0.1 g of EDTA·2Na to dissolve them in the purified water(D). The mixture (A), the mixture (B), the dispersion (C) and thesolution (D) were intimately mixed with one another to obtain a base foran antiphlogistic-analgesic plaster. This base was spread at an amountof 0.1 g/cm² on a nonwoven fabric having weight of 70 g/cm². The surfacewas then covered with a polypropylene film to obtain anantiphlogistic-analgesic plaster according to the present invention,which contained piroxicam in a proportion of 0.25 mg per cm².

Comparative Example 2

A plaster was prepared in the same manner as in Example 6 except thattriethyl citrate was not added, and piroxicam and methylpara-hydroxybenzoate were added to glycerol.

Test Example 2

The plasters obtained in Example 6 and Comparative Example 2 were testedin the same manner as in Test Example 1. The results are shown in FIG.2.

INDUSTRIAL APPLICABILITY

The antiphlogistic-analgesic plasters according to the present inventionare excellent in percutaneous absorption of piroxicam and hence have anexcellent antiphlogistic and analgesic effect.

We claim:
 1. An antiphlogistic-analgesic plaster comprising 0.05-5 wt. %of piroxicam and 0.05-40 wt. % of at least one of triacetin or triethylcitrate incorporated into a plaster base, said plaster comprising awater-soluble polymer, a glycol, a cross-linking agent and water.
 2. Theantiphlogistic-analgesic plaster comprising piroxicam and triacetinand/or triethyl citrate as claimed in claim 1, wherein said basecontains water-soluble polymers, glycols, cross-linking agents, purifiedwater, inorganic powders and surfactants.
 3. Theantiphlogistic-analgesic plaster comprising piroxicam and triacetinand/or triethyl citrate as claimed in claim 2, wherein water-solublepolymers, glycols, cross-linking agents, purified water, inorganicpowders and surfactants are contained in the base in proportions of 1-20wt. %, 1-50 wt. %, 0.01-5 wt. %, 10-90 wt. %, 0-20 wt. % and 0-20 wt. %,respectively.